Introduction

Eosinophilic meningitis is a T-helper type 2 (T _h 2)-mediated host immune reaction triggered by either infectious or noninfectious etiologies leading to central nervous system (CNS) disease. Defined as greater than or equal to 10 eosinophils per microliter of cerebrospinal fluid (CSF) or greater than or equal to 10% of the total CSF leukocyte count, eosinophilic meningitis can be a self-limiting disease or lead to profound morbidity and/or mortality depending on the etiologic agent. Eosinophils are not normally present in the CSF, and the detection of eosinophils suggests a limited differential diagnosis. Noninfectious etiologies of eosinophilic meningitis include neoplastic diseases such as leukemia and lymphoma with CNS involvement such as Hodgkin’s lymphoma, idiopathic hypereosinophilic syndrome, allergic reactions of the meninges to foreign material including ventriculoperitoneal shunts or intraventricular medications (vancomycin, gentamicin), or systemic medication allergies (ibuprofen, ciprofloxacin). Viruses, bacteria, fungi (particularly coccidioidomycosis), and parasites can also cause eosinophilic meningitis ( Table 34.1 ). The combination of increased international travel to endemic areas and importation of parasite vectors such as rodents, snails, slugs, and mollusks to previously nonendemic areas has led to the emergence of parasitic pathogens as a leading cause of eosinophilic meningitis. While neurocysticercosis, schistosomiasis, paragonimiasis, echinococcosis, trichinellosis, and toxocariasis have uncommonly been associated with eosinophilic meningitis, angiostrongyliasis, gnathostomiasis, and baylisascariasis are most commonly known to cause eosinophilic meningitis.

Epidemiology

Angiostrongylus cantonensis (rat lung worm) is the principal pathogen of eosinophilic meningitis in humans. A. cantonensis was first discovered in rats in 1935 in China, and the first human case was diagnosed in Taiwan in 1945. Angiostrongyliasis is a food-borne parasite endemic in Southeast Asia, with particularly high prevalence in Thailand (47% of all reported cases) and China, including Taiwan and Hong Kong (27.22% of all reported cases). Clustering of cases has been documented throughout the region. In 2001, an outbreak was documented in patients in Taiwan who drank raw vegetable juice. More recently, geographic dispersal of A. cantonensis has occurred secondary to transport of infected rats and intermediate hosts on intercontinental ships. A. cantonensis endemicity now extends beyond Southeast Asia to regions in the Pacific basin, South Asia, the Caribbean islands, Australia, Egypt, Nigeria, Côte d’Ivoire, South America, and the United States. An angiostrongyliasis outbreak in Hawaii occurred in 2004–05 and resulted in an increased incidence of eosinophilic meningitis from 0.3 per 100,000 person-years to 2.1 per 100,000 person-years during the cluster period. Furthermore with increasing international travel, cases of angiostrongyliasis have been documented in returning travelers from more than 30 countries. In 2000, 12 travelers returning to the United States from Jamaica were noted to have eosinophilic meningitis secondary to presumed Angiostrongylus cantonensis . Angiostrongyliasis is an emerging pathogen worldwide due to its diversifying geographic distribution.

Gnathostoma spinigerum is a food-borne zoonotic parasite obtained by humans through eating raw or undercooked freshwater fish, brackish-water fish, or other intermediate hosts. The highest prevalence of eosinophilic meningitis due to gnathostomiasis, neurognathostomiasis, occurs in Southeast Asia, particularly Thailand. There is also increasing endemicity in Mexico, Central America, and South America. Human cases of disease have been reported worldwide outside of endemic regions including Cambodia, Laos, Japan, Myanmar, Indonesia, Philippines, Malaysia, China, Sri Lanka, India, Guatemala, Peru, Ecuador, Zambia, and Botswana.

Baylisascaris procyonis is a parasite highly prevalent in raccoon populations worldwide, particularly in the United States. Approximately 70% of adult and 90% of juvenile raccoons in North America are infected with the parasite. Human construction and settlements in wildlife areas have increased human and domestic animal exposure to raccoons. The proximity of raccoon habitat and human homes has led to an increased risk of human disease. Baylisascaris eggs, found in raccoon feces, are durable and can contaminate the environment for years, thus serving as a long-term nidus of infection in areas with dense raccoon populations. Risk factors for human infection are related to contact with infected raccoons or raccoon feces and geophagia of environmental materials contaminated with infected eggs. As a result infants and young children are at particular risk of baylisascariasis due to pica behavior. Human cases have been reported in the literature in California, Illinois, Louisiana, Massachusetts, Michigan, Minnesota, New York, Oregon, and Pennsylvania.

Pathogenesis

A. cantonensis is a small, neurotropic, filiform nematode, tapering at both ends and measuring 16 to 35 mm in length. Rats are the definitive hosts of A. cantonensis . During the life cycle, orally ingested larvae 1 (L1) stage molt a total of four times, generating L2, L3, L4, and L5 larvae, with L3 serving as the infective form in rats and in accidental hosts. L3 larvae penetrate the intestinal tract and travel via the venous hepatoportal circulation to the right ventricle, subsequently traveling through the pulmonary capillaries to the left heart and dispersing through the systemic circulation. Within days of ingestion L3 reach neural tissue. The L3 will molt into L4 and L5 in the neural parenchyma. Rats can survive relatively large infective doses (150 parasites in the brain) without abnormalities. Adult worms leave brain tissue and return to pulmonary arteries through the venous sinuses, superior vena cava, and right ventricle, at which time they reach sexual maturity in the pulmonary arteries 26 to 35 days after infection. The adult worms will subsequently lay eggs in the pulmonary arteries; the eggs hatch into L1, migrate up the bronchial tree, are swallowed, and are excreted in the rodent feces 42 to 45 days postinfection. L1 in the environment will infect intermediate hosts, mollusks (snails and slugs), through ingestion of rodent feces or penetration of the body surface. L1 will molt into infective L3 within the intermediate host, which can also be consumed by paratenic or transport hosts.

Humans are an accidental host of A. cantonensis and typically develop symptoms after an incubation period of a few days to several months following ingestion of raw or inadequately cooked intermediate hosts such as snails, paratenic hosts (crustaceans and frogs), or vegetables contaminated with L3. In human disease, after oral ingestion, L3 penetrate the gastrointestinal tract and are carried via systemic blood vessels to the CNS, at which time they die and do not complete the remaining life cycle. Neural disease is thought to be secondary to direct invasion and migration of the parasite in the neural parenchymal tissue leading to tissue damage, Th2-mediated inflammatory response with eosinophilic predominance, and eosinophilic granulomas surrounding dead worms. Profound cellular infiltrate and cytokine release as a result of dying worms cause increased intracranial pressure within the human host.

Dogs, cats, pigs, and other fish-eating mammals are definitive hosts of G. spinigerum, which can be up to 13 to 55 mm in length. Adult worms form a tumorlike mass in the stomach wall of the definitive mammalian host. The infected animal will shed eggs in its feces into freshwater; these eggs will become embryonated and hatch approximately 7 to 12 days later into L1. Free-swimming L1 are ingested by primary intermediate freshwater crustaceans and will molt into L2. L2-infected crustaceans are eaten by secondary intermediate hosts (freshwater fish, eels, frogs, birds, reptiles), leading to molting of L2 into infective L3. L3 will migrate to muscle tissue and encyst. The infected muscle tissue of the secondary hosts can subsequently be consumed by paratenic hosts (mammals).

Humans are accidental hosts of G. spinigerum and are infected by consuming raw or undercooked primary intermediate hosts (crustaceans), secondary intermediate hosts (freshwater fish), or paratenic hosts (poultry, pigs, snakes, frogs) and less commonly by drinking contaminated water or through direct larval penetration of the skin. In humans, L3 will migrate through subcutaneous tissue, causing intermittent cutaneous migratory skin swelling, and through internal organs including the CNS. L3 will invade the CNS directly through the neural foramina at the skull base or intervertebral foramina along the cranial or spinal nerves and blood vessels. G. spinigerum do not fully develop into adult worms in humans but cause significant disease secondary to diffuse migration. During migration, L3 release proteolytic and hemolytic enzymes as part of the excretory-secretory (ES) product, including matrix metalloproteinases. The incubation period is typically weeks to months, but G. spinigerum can remain dormant for years after initial infection, thus leading to long incubation periods and recurrences.

Baylisascaris procyonis are large intestinal roundworms, range from 9 to 22 cm in length, endemic in the North American raccoon (Procyon lotor) population. Infected adult raccoons shed an average of 20,000 to 26,000 eggs per gram of feces. As a result the host can shed millions of eggs per day into the environment and will have infective potential after 2 to 4 weeks in the environment. Raccoons become infected in two different pathways. Juvenile raccoons ingest B. procyonis eggs, the larvae hatch within the wall of the small intestine and subsequently mature into adult worms within the lumen of small intestines within approximately 63 days. Similarly, paratenic hosts (small birds, rodents, rabbits) become infected by ingesting eggs. Hatched larvae in the intermediate host subsequently migrate through the portal and systemic circulation to other organs, including the CNS, forming larvae encapsulated eosinophilic granulomas within tissue. Paratenic hosts can develop significant disease from larval migration, making them easier prey for adult raccoons. Adult raccoons will ingest L3 encysted tissue of the infected paratenic hosts. After consumption of the cysts, the worms will mature into adult worms in small intestines within a mean of 35 days. Unlike in intermediate hosts, B. procyonis typically does not cause disease in the carnivorous definitive host unless a young raccoon ingests a heavy inoculum. Other carnivores, including domestic dogs and the exotic pet kinkajou, can serve as definitive hosts and are risk factors for further spread of disease to accidental hosts including humans.

The risk of baylisascariasis in humans has increased as the raccoon habitat has become closer in proximity to human populations. Raccoons defecate in communal latrines that are often established near residential homes. B. procyonis eggs are particularly resistant to adverse environmental conditions, and ingestion of only a few eggs, typically less than 5000, is sufficient to cause infection in humans. Young children are at particularly high risk due to their propensity for geophagia. The median age of baylisascariasis in humans is approximately 1 year of age. The incubation period is unknown in humans; however, it is believed that if the inoculum is large enough neural larva migrans can present within 2 to 4 weeks after ingestion of the eggs. B. procyonis are not specifically neurotropic, but due to significant extraintestinal migration, travel to the CNS can occur. Approximately 5% to 7% of larvae migrate to the CNS, penetrating cerebral blood vessels and causing neural larva migrans, at which time the larvae can continue to migrate and grow in the tissue. Because of the significant inoculum of eggs ingested and the relatively smaller brain size to parasite size, baylisascariasis neural larva migrans is particularly devastating in infants and young children.